Cellular interactions between delta and mu opioid receptors (DORs and MORs) are thought to regulate opioid analgesia. However, the neurons in which such interactions could occur within pain neural circuits in vivo remains elusive. In this issue of Neuron, Wang et al. showed that DOR and MOR are present in mostly different populations of nociceptive neurons in the spinal cord and brain, indicating that they may control distinct aspects of pain experience. The cover image illustrates the interactions between two butterflies, DOR and MOR, flying over an opium poppy flower. The butterflies’ wing color patterns show DOR-MOR segregated expression in dorsal horn pain neurons (left) and co-expression in ventral horn neurons constituting motor neural circuits (right). Artwork by Dong Wang.

Morphine and other mu opioid receptor agonists are gold standard analgesics due to their potent inhibitory action on pain processing mechanisms. In this issue, Bardoni et al. provide evidence that the opioid system also exercises broad control over cutaneous mechanosensation, via delta opioid receptors (DORs). The authors show that DOR, depicted in light blue, is expressed by mechanosensory neurons that constitute touch-encoding organs in the skin, including circumferential endings around hair follicles (dark gray). In these neurons, DORs inhibit voltage-gated calcium channels and dampen mechanosensory input to the central nervous system and could represent promising drug targets to combat touch-evoked neuropathic pain.

How different opioid receptor subtypes regulate pain is unclear. It is generally considered that the delta and mu opioid receptors (DOR and MOR, respectively) co-occur in subsets of pain fibers (nociceptors), where they coordinately regulate pain. In this issue of Cell, Scherrer et al. demonstrate that the MOR and DOR are, in fact, expressed by different nociceptor populations. The authors further show that the segregated MOR and DOR distribution is paralleled by a selective functional contribution of the two receptors to the control of heat and mechanical pain, respectively. Photo credit: Opium poppy field in France, by Wolfgang Horlacher. Used under the terms of the GNU Free Documentation License.